This invention relates to an imaging apparatus for use during surgery to locate radiation marked tissue and to create an image of the marked tissue.
Within this application several publications are referenced by arabic numbers enclosed within parentheses. Full citations for these and other references may be found at the end of the specification immediately preceding the claims. The disclosures of all of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.
Precise surgical removal, frequently combined with radiation and chemotherapy, is the most widely used approach in the treatment of adults with solid cancers. Residual subclinical tumor deposits, which may be as large as 1 cubic centimeter even after laparotomy, chemotherapy and radiation can lead to failure in the treatment of patients with primary tumors and inadequate or inappropriate surgery in patients undergoing surgery for recurrent cancer. For example, each year in the United States 155,000 new colorectal cases undergo surgery. Current scanning with computerized tomography and magnetic resonance imaging combined with operative evaluation remain inadequate to determine the true extent of the disease. Although it appears likely that external imaging of radiolabeled antibodies could detect tumor deposits weighing 2-3 grams, a truly useful system must be able to detect tumors weighing less than 1 gram. Therefore, there is a need to develop tools for identifying subclinical tumor deposits at the time of laparotomy.
This need is particularly great for ovarian cancer. Detection of subclinical residual ovarian cancer following chemotherapy is one of the most pressing problems in the management of the 16,000 cases that occur each year in the United States. Recent studies indicate that 50% of patients determined to be free of tumor by standard surgical exploration actually harbor occult residual disease. New monoclonal antibodies have been developed which are highly specific for ovarian cancer. This disease lends itself well to the radioactive marker approach because the cancer tends to remain confined to the surface of the peritoneal cavity and retroperitoneal lymph nodes and because frequent laparotomies, over 300 of which are performed each year at the Memorial Sloan-Kettering Cancer Center, for example, are required as part of its clinical management. Therefore, the ability to detect subclinical residual disease with the use of intraoperative radiation detecting equipment would present a major advance in the management of this disease.
Recent advances have been made in the field of radioimmunolocalization of tumors using radioactive labeled monoclonal antibodies. For example, in one study monoclonal antibody MX35, which reacts with epithelial ovarian cancer, was labeled with Iodine-131. The labeling efficiency of the radioantibody was 92.6%. Three nude mice of the type balb c/nu/nu were injected intraperitoneally and subcutaneously at six weeks of age with serous human ovarian cancer cell line PR-428. This cell line immunohistologically expresses the MX35 antigen. The experiment was performed when the resulting tumors weighed approximately 0.5-2.0 grams. In the experiment, 25 microcuries of Iodine-131 per 25 milligrams of labeled antibody were injected intravenously into the tail vein. A beta probe then measured the radiation emitted at 2, 5 and 7 days after the injection of the marker. The tip of the probe was placed on the surface of the skin at different locations on the body for 20 seconds. The probe counted an average of 6.5 counts/second on the tumor versus an average of 0.5 counts/second on normal tissue. The corresponding tumor sites were verified by surgery. The concentration of the monoclonal antibody were 10 times higher in the tumor than the normal tissue. Thus, this experiment demonstrates the feasibility of detecting a tumor through beta radiation even when there is intervening tissue covering the tumor. Nevertheless, the probe would have to be moved repeatedly to comprehend the extent of each tumor.
As exemplified by this study, a probe for beta rays is known in the prior art, see, for example, U.S. Pat. No. 5,008,546 ("'546") to Mazziotta et al. Since the beta probe of Mazziotta et al. '546 is sensitive only to beta rays, a beta probe in close proximity to the tissue can image small superficial tumor deposits without any interference from background gamma rays. Background gamma radiation can obscure the radiation normally received from beta markers. However, scanning a large area, for example, the surface of the peritoneal cavity, with a beta probe during surgery may be too time consuming. Therefore, a wider field of detection is needed.
Other studies discuss difficulties with background radiation. Barber et al. and Woolfenden et al. (1-3) developed and used several intraoperative and intraluminal gamma probes for gynecologic and lung tumor detection using Cobalt-57 labeled bleomycin as a tumor marker. These attempts were only partially successful due mainly to the background gamma rays emitted from distant organs with high radioactive uptake. A Cadmium-Tellurium semiconductor gamma detector, for example, can be used. Such a detector is commercially available from the Neoprobe Corporation of Columbus, Ohio. This detector is 15 millimeters in diameter and 2 millimeters thick. Due to its thinness, the detector is only efficient in detecting relatively low energy gamma rays or X-rays, for example, X-rays of 30 kiloelectron volts emitted from Iodine-125. This severely limits the application of this probe to only isotopes that emit low energy gamma rays or X-rays. Since these low energy gamma rays are less effective in penetrating tissue than higher energy gamma rays, the problem of background activity is reduced somewhat. Accordingly, several groups that have used such a device in surgery were successful in locating tumors (4-8). Dr. A. Cohen of the Memorial Sloan-Kettering Cancer Center recently reported the experience of a multicenter trial with the Neoprobe detector in 105 patients using Iodine-125 labeled with B72.3 monoclonal antibodies confirming the previous work. However, this detector is still sensitive to background radiation. Additionally, the Neoprobe detector is very sensitive to temperature changes and to background radiation when pointed at a highly radioactive area. Also, this probe is too large for sites within a small operative field.
As exemplified in these studies, intraoperative gamma cameras and probes are known in the art, see for example, U.S. Pat. No. 4,791,300 ("'300") to Yin. However, Yin '300 is designed to detect only gamma radiation which travels much farther in tissue than some other types of radiation, such as beta rays. Therefore, there is a need for a camera that can be placed very close, that is, within millimeters of the source of the radiation. Additionally, if a camera could be placed close to the source of radiation, the effects of background radiation are reduced.
In another study, Reinhardt et al. (9, 10) used a semiconductor detector to localize tumor remnants which were visually difficult to distinguish from normal brain tissue. Reinhardt et al. used P-32 as a tumor marker. This isotope emitted only beta rays and not gamma rays. Most other beta emitting isotopes emit gamma emissions as well; therefore a semiconductor probe would still have the difficulty of any other gamma probe when used with commonly used isotopes for tumor marking that emit gamma rays in addition to beta rays, for example, Iodine-131. Additionally, they were not successful in detecting highly malignant brain cancers because P-32 was not a good tumor marker. They concluded that other specific tumor markers such as monoclonal antibodies are needed.
In another recent study, Barber et al. (11) compared a Sodium-Iodine-Thallium gamma probe with a gamma camera for the task of detecting radiolabeled tumors in a water phantom. They concluded that 15 seconds of counting with a gamma probe located a few centimeters away is superior to 10 minutes of imaging with a conventional gamma camera placed 10-20 centimeters from the source when the background radiation is uniform. This study also showed that if the conventional gamma camera is positioned less than 5 centimeters from the source, tumor detectability would improve substantially. Also, Hickernell et al. (12) developed a dual, coaxial, Sodium-Iodine-Thallium gamma probe in order to take account of the background counts by using an outer detector. Based on computer simulations this probe should be more effective in identifying tumors only if the probe is centered on the tumor. Additionally, Hartsough et al. (13) have built an imaging probe using a two dimensional array of 21 Cadmium-Tellurium detectors, where each detector has dimensions of 3 millimeters by 3 millimeters and the detectors are located behind a parallel hole collimator. Although this imaging probe has low efficiency due to its collimator and has only 21 imaging elements which are not sufficient to form a realistic image, this imaging probe is expected to improve the discrimination of tumor counts from background counts. These studies also show the efficacy of placing the camera's detector element as close as possible to the area of interest. Although these cameras and probes present partial solutions to reduce the effects of background radiation, each of these devices have their own limitations.
Finally, beta cameras which are less sensitive to gamma radiation are known in the art. For example, see Ljundggren and Strand (14). The Ljundggren and Strand camera, which is constructed with a scintillator, a rigid fiber optic face plate, a photocathode, a microchannel plate and a resistive anode, however, is too large and inflexible to be used in conjunction with a laparoscopic procedure. Also, the microchannel plate of the Ljundggren and Strand camera uses 10,000 volts of electricity making the camera relatively dangerous for intraoperative use. Additionally, this tabletop camera was built for in-vitro imaging of laboratory animal tissues.